Glutamate receptors play a role in numerous neurological, neurodegenerative, psychiatric, and psychological disorders, and a variety of mammalian disease states are associated with aberrant activity of these receptors. Glutamate receptors have been classified as either “ionotropic” or “metabotropic”. Ionotropic receptors are directly coupled to the opening of cation channels in the cell membranes of the neuron. Metabotropic receptors belong to the family of G-protein-coupled receptors and are coupled to systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in ion channel function.
Metabotropic glutamate receptors (mGluRs) are divided into three groups based on amino acid sequence homology, transduction mechanism and binding selectivity: Group I, Group II and Group III. Group I includes metabotropic glutamate receptors 1 and 5 (mGluR1 and mGluR5), Group II includes metabotropic glutamate receptors 2 and 3 (mGluR2 and mGluR3), and Group III includes metabotropic glutamate receptors 4, 6, 7, and 8 (mGluR4, mGluR6, mGluR7 and mGluR8). Each mGluR type may be found in several subtypes. For example, subtypes of mGluR1 include mGluR1a, mGluR1b and mGluR1c.
It is only recently that researchers have begun to elucidate physiological roles for each mGluR group. For example, Group II metabotropic glutamate receptors (mGluII), including mGlu2 and mGlu3 receptors, are inhibitory autoreceptors located primarily on glutamatergic afferents throughout the mammalian brain where they decrease excitatory glutamate transmission (Cartmell and Schoepp, J Neurochem 75:889-907, 2000). GABAB receptors, which share close structural and functional homology to mGluII receptors (Schoepp, J. Pharmacol. Exp. Ther., 299:12-20, 2001), also negatively regulate glutamate transmission. Recently, activation of mGluII and GABAB receptors was shown to decrease excitatory glutamate transmission in the ventral tegmental area (VTA) and nucleus accumbens (NAcc) (Bonci et al., Eur. J. Neurosci., 9:2359-2369, 1997; Xi et al., J. Pharmacol. Exp. Ther., 300:162-171, 2002; Erhardt et al., Naunyn Schmiedebergs Arch. Pharmacol., 365:173-180, 2002), suggesting that these receptors may regulate the activity of the brain's reward circuitry. Accordingly, LY314582 and CGP44532, agonists at mGluII and GABAB receptors respectively, were shown to elevate intracranial self-stimulation (ICSS) reward thresholds in drug-naïve rats (Macey et al., Neuropharmacology, 40:676-685, 2001; Harrison et al., Psychopharmacology, 160:56-66, 2002), demonstrating that mGluII and GABAB receptors negatively regulate brain reward function.
Moreover, there is accumulating evidence that the function of mGluII and GABAB receptors increases during the development of drug dependence. For example, prolonged morphine, cocaine or amphetamine treatment increased inhibitory regulation of glutamate transmission by mGluII and GABAB receptors located in the VTA and NAcc (Manzoni and Williams, J. Neurosci., 19:6629-6636, 1999; Xi et al., Soc. Neurosci., Abstr 27: 2596, 2001; Giorgetti et al., Neuroscience, 109:585-595, 2002).
Attempts at elucidating the physiological roles of Group I mGluRs suggest that activation of these receptors elicits neuronal excitation. Evidence indicates that this excitation is due to direct activation of postsynaptic mGluRs, but it also has been suggested that activation of presynaptic mGluRs occurs, resulting in increased neurotransmitter release (Baskys, Trends Pharmacol. Sci. 15:92, 1992, Schoepp, Neurochem. Int. 24:439, 1994, Pin et al., Neuropharmacology 34:1, 1995.) Thus, it has been proposed that antagonists for the Group I mGluRs may be useful in treating neurological disorders such as senile dementia, Parkinson's disease, Alzheimer's disease, Huntington's Chorea, pain, epilepsy, and head trauma.
However, less is known about the potential therapeutic benefits that may be realized as a result of simultaneous antagonism of mGluRs belonging to different groups. Furthermore, little is known about whether antagonists of mGluRs are useful for treating disorders such as substance abuse and depression. The invention addresses these issues and further provides related advantages.